4.3.3 Major pharmacological theories
Major Aetiological Theories Underpinned by Pharmacological Mechanisms
There is a range of aetiological theories that attempt to explain the underlying causes of psychiatric and neurological disorders, many of which are underpinned by pharmacological mechanisms. These theories are usually supported by extensive research, including animal studies, human brain imaging and psychopharmacological treatments. Some of the major theories include the monoamine hypothesis of depression, the glutamate hypothesis of schizophrenia, the cholinergic hypothesis of Alzheimer’s disease, the dopamine hypothesis of Parkinson’s disease and the opioid hypothesis of pain. These theories provide a conceptual framework for understanding the effects of drugs on the brain and the underlying mechanisms of disease, and they are the basis for the development of new and innovative treatments for a wide range of conditions.
| Pharmacological theory: | Summary: |
| Dopamine hypothesis | The dopamine hypothesis suggests that imbalances in the dopamine system in the brain play a role in the development of certain psychiatric disorders, particularly schizophrenia. |
| Biogenic amine hypothesis | The dopamine hypothesis posits that the dysregulation of dopamine neurotransmission is a key factor in the development of schizophrenia and other psychoses. |
| Cholinergic hypothesis (cognition) | The Cholinergic Hypothesis states that a deficiency in acetylcholine, a neurotransmitter in the central nervous system, is responsible for the cognitive symptoms seen in certain disorders, such as Alzheimer’s disease. |
| Cholinergic-adrenergic hypothesis (mood) | The cholinergic-adrenergic hypothesis suggests that the balance between acetylcholine and adrenaline/noradrenaline neurotransmitter systems is important in regulating mood. |
| Glutamatergic hypothesis | The glutamatergic hypothesis proposes that alterations in the glutamate neurotransmitter system play a role in the pathogenesis of various psychiatric and neurological disorders, including schizophrenia, depression, and bipolar disorder. |
| Amyloid cascade hypothesis | The amyloid cascade hypothesis proposes that the accumulation of beta-amyloid peptides in the brain triggers a series of events leading to neuronal damage and eventually neuronal death, resulting in the development of Alzheimer’s disease. |
Dopamine hypothesis:
The dopamine hypothesis is a theory that suggests that the major aetiology of schizophrenia is a dysfunction in the dopamine neurotransmitter system. According to this hypothesis, there is an overactivity in the mesolimbic dopamine pathway, which is thought to be responsible for positive symptoms of schizophrenia, such as hallucinations and delusions. This theory also suggests that the mesocortical dopamine pathway, which is involved in the regulation of motivation and cognition, is underactive in patients with schizophrenia. The dopamine hypothesis of schizophrenia has been supported by a large body of evidence from clinical and preclinical studies, as well as from the therapeutic effects of dopamine antagonists, such as antipsychotics. However, it is now widely acknowledged that the dopamine hypothesis is only a part of a much more complex and nuanced understanding of the aetiology of schizophrenia and other psychiatric disorders and that the role of dopamine in these disorders is likely much more complex than originally thought (Schmaal, 2017).
Biogenic amine hypothesis:
The biogenic amine hypothesis proposes that changes in the levels or activity of monoamine neurotransmitters, such as dopamine, norepinephrine, and serotonin, are involved in the aetiology of various psychiatric disorders. This theory suggests that imbalances in these neurotransmitters can lead to symptoms such as depression, anxiety, and mania. This hypothesis is based on the observation that certain drugs that modulate the levels of these neurotransmitters, such as antidepressants and antipsychotics, are effective in treating these disorders (Coppen, 1967).
Cholinergic hypothesis (cognition):
The cholinergic hypothesis of cognition is a theory that suggests that the acetylcholine (ACh) neurotransmitter system in the brain is particularly involved in the regulation of cognitive processes such as attention, learning, and memory. According to this hypothesis, a deficiency in the activity of the ACh system is thought to underlie cognitive impairment in conditions such as Alzheimer’s disease, as well as age-related cognitive decline. The cholinergic hypothesis proposes that increasing the availability of ACh in the brain, either by enhancing its synthesis, release, or degradation, can modulate cognitive processes and improve cognitive function. This hypothesis has been supported by a number of studies, which have shown that drugs that enhance ACh function, such as cholinesterase inhibitors, can improve memory in patients with Alzheimer’s disease. However, more recent studies have also shown that the effects of cholinergic drugs on cognition are complex and may depend on other neurotransmitter systems and brain regions, suggesting that the cholinergic hypothesis may not fully explain the mechanisms underlying cognitive processes (Sarter, 2001).
Cholinergic-adrenergic hypothesis (mood):
The Cholinergic-Adrenergic Hypothesis of Mood postulates that a balance between the activities of the cholinergic and adrenergic systems in the brain is crucial in regulating mood. An over-activity of the cholinergic system and/or a decrease in adrenergic activity is believed to lead to depression, while an over-activity of the adrenergic system and/or a decrease in cholinergic activity is thought to lead to mania. This hypothesis suggests that mood-stabilizing drugs that alter the balance between these two systems, such as lithium and valproate, may help to regulate mood swings in conditions like bipolar disorder (Drevets, 2008).
Glutamatergic hypothesis:
The Glutamatergic hypothesis suggests that alterations in the glutamate neurotransmitter system contribute to the development and symptoms of psychiatric disorders such as schizophrenia, depression, and anxiety. The hypothesis proposes that a dysregulation of the glutamate system leads to changes in glutamate signalling and synaptic plasticity, which are thought to play a role in the pathophysiology of these disorders (Honda, 2017).
Amyloid cascade hypothesis:
The Amyloid cascade hypothesis is a theoretical model that proposes the accumulation of amyloid-β peptide in the brain as a central trigger in the pathogenesis of Alzheimer’s disease (AD). According to this hypothesis, the production and accumulation of amyloid-β in the brain, along with oxidative stress, inflammation, and neurodegeneration, leading to synaptic dysfunction and neuronal death. This, in turn, results in the progressive memory loss and cognitive decline characteristic of AD. The Amyloid cascade hypothesis has been the dominant theory of AD for several decades and continues to inform current research efforts to understand and treat the disease. However, more recent studies have highlighted the limitations of this hypothesis, and the search for new and more comprehensive models of AD pathogenesis continues (Selkoe, 2002).
References:
(1) Coppen, A. & Walk, J. (1967). The biogenic amine hypothesis of affective disorders: A review of supporting evidence. Journal of Psychopharmacology, 1(1), 67-80.
(2) Drevets, W. C., Price, J. L., & Furey, M. L. (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Structure and Function, 213(1-2), 93-118. doi: 10.1007/s00429-008-0189-x
(3) Honda, M., & Mochizuki, H. (2017). The glutamatergic hypothesis of psychiatric disorders. Frontiers in pharmacology, 8, 104. https://doi.org/10.3389/fphar.2017.00104
(4) Sarter, M., Givens, B., & Bruno, J. P. (2001). The cognitive neurosciences and the cholinergic hypothesis for cognitive aging and neurodegeneration. Neuroscience and Biobehavioral Reviews, 25(2), 3-22.
(5) Schmaal, L., van Erp, T. G. M., Sérrano-Blanco, A., Abe, Y., Alonso, P., Anticevic, A., … & Turner, J. A. (2019). The dopamine hypothesis of major psychiatric disorders: past and current status. World Psychiatry, 18(2), 115-124.
(6) Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 298(5594), 789-794.